What are the causes of microcytic hypochromic anemia?

Causes of Microcytic Hypochromic Anemia

Microcytic hypochromic anemia is primarily caused by nutritional iron deficiency, iron loss from gastrointestinal disease, iron malabsorption, hemoglobinopathies (including thalassemia syndromes), and severe anemia of chronic disease. 1

Primary Causes

Iron-Related Disorders (Most Common)

• Iron deficiency anemia represents approximately 80% of all microcytic anemias worldwide and is the most common cause in both developing and industrialized countries 2

  • Results from nutritional deficiency, gastrointestinal blood loss, malabsorption, or increased physiologic demands 1, 3
  • High-risk populations include infants, toddlers, premenopausal women, pregnant women, and elderly patients 2

• Anemia of chronic disease (ACD) causes functional iron deficiency through iron sequestration rather than true depletion 4, 2

  • Iron absorption and release are blocked as a nonspecific defense mechanism 2
  • Characterized by elevated ferritin with low serum iron 4
  • Particularly significant in hospitalized patients and elderly populations 2

Hemoglobinopathies

• Thalassemia syndromes are a major cause of microcytic hypochromic anemia 1, 5

  • Distinguished from iron deficiency by normal or elevated serum iron and normal free erythrocyte protoporphyrin levels 5
  • Thalassemia trait (TT) requires differentiation from IDA, as clinical management differs significantly 6

• Hemoglobin E disorders produce microcytic anemia with normal or elevated serum iron 5

Lead Toxicity

• Lead poisoning causes microcytic anemia through impaired heme synthesis 5
  • Characterized by low serum iron and elevated free erythrocyte protoporphyrin 5

Genetic Disorders of Iron Metabolism and Heme Synthesis

When ferritin is elevated and/or transferrin saturation is abnormal, or when anemia is refractory to iron supplementation, consider genetic disorders of iron metabolism or heme synthesis. 1

Defects in Iron Absorption and Transport

• Iron refractory iron-deficiency anemia (IRIDA) from TMPRSS6 defects causes anemia unresponsive to oral iron 1, 7

• Hypotransferrinemia from transferrin (TF) gene defects impairs iron delivery to erythroblasts 1, 7

• DMT1 deficiency (SLC11A2 defects) causes anemia with paradoxical systemic iron loading 1, 7

  • Presents at birth with microcytic anemia and increased transferrin saturation 1
  • Liver iron loading develops despite normal or mildly increased ferritin 1

Defects in Erythroblast Iron Uptake

• STEAP3 deficiency impairs ferroreductase activity, preventing Fe3+ reduction to Fe2+ in erythroblast endosomes 1, 7

Sideroblastic Anemias (Mitochondrial Iron Utilization Defects)

• SLC25A38 deficiency causes severe congenital sideroblastic anemia 1

  • Presents with transfusion-dependent microcytic hypochromic anemia in childhood 1
  • Bone marrow shows ring sideroblasts with elevated ferritin and transferrin saturation 1
  • Iron overload is of greater consequence than the anemia itself and can lead to severe morbidity and mortality if unrecognized 1

• X-linked sideroblastic anemia with ataxia (XLSA/A) from ABCB7 defects causes mild microcytic anemia with cerebellar ataxia 1

• ALAS2 deficiency represents loss-of-function defects in the first enzyme of heme synthesis 1

Defects in Iron Recycling

• Iron recycling disorders impair the release of iron from macrophages for erythropoiesis 7

Critical Clinical Pitfalls

• Do not start empiric oral iron therapy when ferritin is elevated (>382 μg/L), as this could worsen iron overload in sideroblastic anemia or genetic disorders 4

• Family history of anemia refractory to iron supplementation, neurologic disease, or skin photosensitivity should raise suspicion for genetic disorders 1

• Differentiation between iron deficiency anemia and anemia of chronic disease is clinically crucial, as management strategies differ fundamentally 2

  • Iron deficiency requires identification and correction of the underlying cause 2
  • ACD treatment focuses on eliminating the underlying chronic disorder 2

• Serum ferritin may be elevated in inflammatory conditions despite concurrent iron deficiency, potentially masking true iron depletion 4